CN113491695A - Lovatinib pharmaceutical composition, preparation method and application thereof - Google Patents
Lovatinib pharmaceutical composition, preparation method and application thereof Download PDFInfo
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- CN113491695A CN113491695A CN202110173085.3A CN202110173085A CN113491695A CN 113491695 A CN113491695 A CN 113491695A CN 202110173085 A CN202110173085 A CN 202110173085A CN 113491695 A CN113491695 A CN 113491695A
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- 208000018556 stomach disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229950006605 varlitinib Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention provides a pharmaceutical composition of Ranuncutinib, a preparation method and application thereof. The invention discloses a pharmaceutical composition of Ranuncutinib, which comprises the following components: an active drug and calcium bicarbonate, wherein the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy represented by formula I]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof. The preparation method of the pharmaceutical composition of the invention has the advantages of good dissolution rate, good stability, simple preparation process and suitability for industrial production, and the dissolution rate of the pharmaceutical composition of the invention can reach more than 90% within 15 minutes.
Description
The applicant claims the priority of the prior application entitled "a pharmaceutical composition of Rankine, its preparation method and use" filed on 18.3.2020 by the patent application No. 202010190116.1 from the applicant to the intellectual Property office of China. The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of Ranuncutinib, and a preparation method and application thereof.
Background
LENVIMA (lunvatinib), chemical name 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide. Lomcatinib is a multi-target drug, is an oral multi-RTK inhibitor developed by medical instruments, and can inhibit the kinase activity of other angiogenesis promoting and oncogenic signaling pathway related RTKs (including receptors PDGFR, KIT and RET of platelet derived growth factor [ PDGF ]) involved in tumor proliferation, and can also selectively inhibit Vascular Endothelial Growth Factor (VEGF) receptors (VEGFR1, VEGFR2, VEGFR3) and Fibroblast Growth Factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR 3). Lovatinib is approved for marketing in the United states 2 months 2015, Japanese PMDA approved for marketing 5 months 2015, and EMEA approved for marketing 5 months 2015.
CN 200580026468.7 discloses a ranvatinib tablet, comprising a stabilizer such as magnesium oxide, calcium oxide, anhydrous sodium carbonate or sodium bicarbonate, etc.; and a gelation inhibitor such as light silica, calcium silicate, magnesium silicate or magnesium aluminosilicate, etc., which solves the problem of incomplete dissolution caused by gelation during dissolution of the crude drug, but the stability of the composition has a certain problem.
CN 201080030508.6 discloses a ranvatinib capsule, which comprises calcium carbonate and magnesium carbonate, wherein the granule is prepared by wet granulation, and the stability of the obtained composition is improved by filling with hypromellose capsule shell. However, the dissolution rate of the composition is reported to be lower in the first 15min by CN 106551935A.
PCT patent application WO 2006/030826 discloses that when ranvatinib is used as an active ingredient to prepare a pharmaceutical composition, the pharmaceutical composition is decomposed under the conditions of humidification and heating storage, and when the pharmaceutical composition absorbs moisture, the surface of the composition is gelled to generate extremely strong viscosity, which causes the dissolution delay of the ranvatinib, and affects the onset and absorption of the drug. To overcome such problems, LENVIMATM of marketed Japan Weining company uses a combination of Rankine and calcium carbonate, which is a common excipient in effervescent tablets, and orally enters the gastrointestinal tract to generate a large amount of bubbles under the action of gastric acid, so that the Rankine molecules are separated from each other to prevent gelation thereof. However, oral administration of calcium carbonate may cause constipation and gastric bloating, and is not suitable for direct administration to the elderly and patients with gastric diseases such as gastric ulcer (see "calcium carbonate" section on page 86 of the fourth edition of the handbook of pharmaceutical excipients (the Master translation of Zheng Junmin et al)), which may account for a significant proportion of patients with tumors.
At present, a preparation of ranvatinib which is complete in dissolution, good in stability, suitable for patent medicine, simple in process and suitable for industrial production is urgently needed to be found.
Disclosure of Invention
The invention aims to overcome the defects of unsatisfactory dissolution effect, poor stability, complex preparation process, unsuitability for industrial production and the like of a Rankine preparation in the prior art, and provides a Rankine pharmaceutical composition, a preparation method and application thereof. The preparation method of the pharmaceutical composition of the invention has the advantages of good dissolution rate, good stability, simple preparation process and suitability for industrial production, and the dissolution rate of the pharmaceutical composition of the invention can reach more than 90% within 15 minutes.
The invention provides a pharmaceutical composition of Ranuncutinib, which comprises the following components: an active drug and calcium bicarbonate, wherein the active drug comprises 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide represented by formula I and/or a pharmaceutically acceptable salt thereof;
preferably, the pharmaceutical composition of ranvatinib comprises the following components: the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I or a pharmaceutically acceptable salt thereof;
preferably, the pharmaceutical composition of ranvatinib further comprises one, two or more of a diluent, a disintegrant, a binder and a lubricant.
The invention provides a pharmaceutical composition of varenib, preferably comprising the following components: 1-30% of active medicine, 10-50% of calcium bicarbonate, 10-50% of diluent, 10-30% of disintegrating agent, 0-5% of adhesive and 0.5-5% of lubricant; the active medicine contains 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I and/or pharmaceutically acceptable salts thereof; the percentage refers to weight percentage, and the weight percentage refers to the weight of a single component accounting for the total weight of the composition;
preferably, the pharmaceutical composition of varlitinib, preferably comprises the following components: 1-30% of active medicine, 10-50% of calcium bicarbonate, 10-50% of diluent, 10-30% of disintegrating agent, 0-5% of adhesive and 0.5-5% of lubricant; the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I or pharmaceutically acceptable salt thereof; the percentage refers to weight percentage, and the weight percentage refers to the weight of a single component accounting for the total weight of the composition;
according to an embodiment of the invention, the pharmaceutically acceptable salt of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide represented by formula I is preferably the mesylate salt of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide.
According to an embodiment of the invention, the diluent is selected from one or more of lactose, microcrystalline cellulose, starch (e.g. corn starch), mannitol, glucose, sucrose, modified starch (e.g. pregelatinized starch) and microcrystalline cellulose (e.g. silicified microcrystalline cellulose); preferably one or more of lactose, mannitol, starch, microcrystalline cellulose and pregelatinized starch. For example a mixture of mannitol and starch, a mixture of starch and lactose, mannitol and/or microcrystalline cellulose.
According to an embodiment of the invention, the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, effervescent disintegrant, calcium carboxymethylcellulose and carboxymethylcellulose. Exemplary is low substituted hydroxypropyl cellulose.
According to an embodiment of the invention, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone. Exemplary is hydroxypropyl cellulose.
According to an embodiment of the invention, the lubricant is selected from one or more of talc, magnesium stearate, hydrogenated castor oil, glyceryl behenate and aerosil. Exemplary is talc.
According to an embodiment of the present invention, the content of the active drug in the pharmaceutical composition of ranvatinib is preferably 1% to 10%, such as 2%, 4%, 4.9%, 5%, 10%, 15%, 20%, 25%, 30% or any of the two values mentioned above in combination.
According to an embodiment of the present invention, the amount of calcium bicarbonate in the pharmaceutical composition of ranvatinib is preferably 10.0% to 50.0%, and more preferably 15.0% to 40.0%, such as 10.0%, 20.0%, 33.0%, 40.0%, 50.0%, or any two of the above two values in combination.
According to an embodiment of the present invention, the amount of the diluent in the pharmaceutical composition of ranvatinib is preferably 15.0% to 50.0%, more preferably 20.0% to 40.0%, such as 17.0%, 19.1%, 22.0%, 24.1%, 25.0%, 30.0%, 31.1%, 35.0%, 44.1%, 45.0%, 49.1% or any one of the two values mentioned above in combination.
According to an embodiment of the present invention, the content of the disintegrant in the pharmaceutical composition of ranvatinib is preferably 20.0% to 30.0%, such as 15.0%, 20.0%, 25.0%, 30.0% or any one of the two values mentioned above in combination.
According to an embodiment of the present invention, the content of the binding agent in the pharmaceutical composition of ranvatinib is preferably 1.0% to 4.0%, such as 0.5%, 1.0%, 2.0%, 2.5%, 3.0%, 3.5%, 4.5% or any two of the above-mentioned values in combination.
According to an embodiment of the present invention, the amount of the lubricant in the pharmaceutical composition of ranvatinib is preferably 1.0% to 4.0%, such as 0.5%, 1.0%, 2.0%, 2.5%, 3.0%, 3.5%, 4.5% or any two of the above two values in combination.
According to an embodiment of the present invention, said pharmaceutical composition of ranvatinib, preferably comprises the following components: 1.0-10.0 percent of active medicine, 10.0-50.0 percent of calcium bicarbonate, 15.0-50.0 percent of diluent, 20.0-30.0 percent of disintegrant, 1.0-4.0 percent of adhesive and 1.0-4.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
according to an embodiment of the present invention, said pharmaceutical composition of ranvatinib, further preferably comprises the following components: 4.9 percent of active medicine, 10.0 to 50.0 percent of calcium bicarbonate, 15.0 to 50.0 percent of diluent, 20.0 to 30.0 percent of disintegrant, 3.0 percent of adhesive and 3.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
the invention also provides a pharmaceutical composition of Ranuncutinib, which comprises the following components: 1.0-30.0 percent of active drug, 10.0-50.0 percent of calcium bicarbonate, 10.0-50.0 percent of diluent, 10.0-30.0 percent of disintegrant, 0-5.0 percent of adhesive and 0.5-5.0 percent of lubricant; the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I or a pharmaceutically acceptable salt thereof, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc.
According to an embodiment of the present invention, said pharmaceutical composition of ranvatinib, preferably, consists of: 1.0-10.0 percent of active medicine, 10.0-50.0 percent of calcium bicarbonate, 15.0-50.0 percent of diluent, 20.0-30.0 percent of disintegrant, 1.0-4.0 percent of adhesive and 1.0-4.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc.
According to an embodiment of the present invention, said pharmaceutical composition of ranvatinib, further preferably consisting of: 4.9 percent of active medicine, 10.0 to 50.0 percent of calcium bicarbonate, 15.0 to 50.0 percent of diluent, 20.0 to 30.0 percent of disintegrant, 3.0 percent of adhesive and 3.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc.
According to an embodiment of the present invention, the pharmaceutical composition of ranvatinib, still further preferably any one of the following formulations:
the formula I is as follows: 4.9% of active drug, 33.0% of calcium bicarbonate, 15.1% of microcrystalline cellulose, 16.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and a second formula: 4.9% of active drug, 10.0% of calcium bicarbonate, 25.1% of microcrystalline cellulose, 24.0% of mannitol, 30.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and the formula III: 4.9% of active drug, 20.0% of calcium bicarbonate, 22.1% of microcrystalline cellulose, 22.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
the formula four: 4.9% of active drug, 40.0% of calcium bicarbonate, 12.1% of microcrystalline cellulose, 12.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and a fifth formula: 4.9% of active drug, 50.0% of calcium bicarbonate, 10.1% of microcrystalline cellulose, 9.0% of mannitol, 20.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
according to an embodiment of the present invention, the pharmaceutical composition of ranvatinib is preferably a solid formulation, such as a capsule, tablet, granule, powder, sustained release formulation or drop pill; preferably, the sustained-release agent is a sustained-release pellet capsule or a sustained-release tablet.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
step 1: mixing an active drug, calcium bicarbonate, a diluent and a disintegrant to obtain a premix;
step 2: granulating and drying the premix obtained in the step 1 and an adhesive to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles obtained in the step (2), and then mixing with a lubricant to obtain the pharmaceutical composition.
According to an embodiment of the invention, the active drug, diluent, disintegrant and lubricant are all selected and used in the amounts as indicated above.
According to an embodiment of the invention, the calcium bicarbonate has the amount as indicated above.
According to an embodiment of the present invention, in step 1, the wet granulation may be performed in a wet granulator.
According to an embodiment of the invention, in step 2, the moisture content of the dry granules is less than 2%, said percentage being the weight of water based on the total weight of the dry granules.
According to an embodiment of the present invention, in step 3, the mixing may be performed in a three-dimensional mixer.
According to an embodiment of the present invention, the pharmaceutical composition obtained in step 3 may be further encapsulated to obtain a capsule.
The invention also provides the preparation method of the pharmaceutical composition of the Rankine.
The invention also provides a pharmaceutical preparation of the Rankine, which contains the pharmaceutical composition of the Rankine.
According to an embodiment of the present invention, the formulation may be a solid formulation, such as a capsule, a tablet, a granule, a powder, a sustained-release agent, or a dropping pill; preferably, the sustained-release agent is a sustained-release pellet capsule or a sustained-release tablet.
According to an embodiment of the invention, the dissolution rate of the pharmaceutical formulation of Rankine at 15min is not less than 90%, such as more than 90%. Preferably, the dissolution rate is obtained by taking a hydrochloric acid solution as a dissolution medium of the pharmaceutical formulation of Rankine.
The invention also provides a preparation method of the Lovatinib pharmaceutical preparation, and the preparation method comprises the preparation of the pharmaceutical composition.
Preferably, the preparation method of the pharmaceutical formulation of Ranvatinib comprises the preparation of the pharmaceutical composition described above.
Preferably, the preparation method of the pharmaceutical preparation comprises: and (3) filling the medicinal composition obtained in the step (3) in the preparation method of the medicinal composition into capsules to obtain capsules.
The invention also provides application of the pharmaceutical composition and/or the preparation in preparing a medicament for treating and/or preventing tumor-related diseases. Preferably, the tumor-related disease may be thyroid cancer, non-small cell lung cancer, melanoma, hypopharynx cancer, esophageal cancer, gastric cancer, large intestine cancer, hepatocellular cancer, renal cell cancer, pancreatic cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myelogenous leukemia, neuroma, glioma, and the like.
The present invention also provides a method for preventing and/or treating the above-mentioned tumor-associated diseases, comprising administering said pharmaceutical composition and/or formulation to a patient, e.g. a human, in need thereof.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The invention has the advantages of
The invention can provide the pharmaceutical composition of the Lunvatinib which has good stability and the dissolution rate of more than 90 percent within 15min, and the pharmaceutical composition has simple preparation process and is suitable for industrialized production.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Examples 1 to 5
Step 1: the mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (compound of formula I) (hereinafter referred to as compound A, referred to the method reported in CN1478078A, purity: 99.83%), microcrystalline cellulose, calcium bicarbonate, low-substituted hydroxypropyl cellulose, and mannitol were mixed in the proportions shown in Table 1 using a high-speed wet granulator to obtain a premix;
step 2: taking an aqueous solution of hydroxypropyl cellulose (the concentration of the hydroxypropyl cellulose is 12%) as a binding agent, and granulating and drying the premix obtained in the step 1 and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 1 examples 1-5 component ratio table
Example 6
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium hydrophosphate, low-substituted hydroxypropyl cellulose and mannitol by adopting a high-speed wet granulator according to the proportion shown in Table 2 to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 2 comparative example 1 component ratio table
| Composition (I) | Ratio (% by weight) |
| Compound A | 4.9 |
| Microcrystalline cellulose | 15.1 |
| Mannitol | 16.0 |
| Calcium hydrogen phosphate | 33.0 |
| Low-substituted hydroxypropyl cellulose | 25.0 |
| Hydroxypropyl cellulose | 3.0 |
| Talcum powder | 3.0 |
| Total of | 100 |
Example 7
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium phosphate, low-substituted hydroxypropyl cellulose and mannitol in a ratio shown in Table 3 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 3 example 7 table of the proportions of the components
Example 8
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium citrate, low-substituted hydroxypropyl cellulose and mannitol in a ratio shown in Table 4 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 4 example 8 table of the proportions of the components
| Composition (I) | Ratio (% by weight) |
| Compound A | 4.9 |
| Microcrystalline cellulose | 15.1 |
| Mannitol | 16.0 |
| Calcium citrate | 33.0 |
| Low-substituted hydroxypropyl cellulose | 25.0 |
| Hydroxypropyl cellulose | 3.0 |
| Talcum powder | 3.0 |
| Total of | 100 |
Example 9
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium citrate, calcium hydroxide, low-substituted hydroxypropyl cellulose and mannitol in a proportion shown in Table 5 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 5 example 9 component ratio table
| Composition (I) | Ratio (% by weight) |
| Compound A | 4.9 |
| Microcrystalline cellulose | 15.1 |
| Mannitol | 16.0 |
| Calcium citrate | 32.1 |
| Calcium hydroxide | 0.9 |
| Low-substituted hydroxypropyl cellulose | 25.0 |
| Hydroxypropyl cellulose | 3.0 |
| Talcum powder | 3.0 |
| Total of | 100 |
Example 10
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium gluconate, low-substituted hydroxypropyl cellulose and mannitol in a ratio shown in Table 6 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 6 table of the proportions of each component in example 10
| Composition (I) | Ratio (% by weight) |
| Compound A | 4.9 |
| Microcrystalline cellulose | 15.1 |
| Mannitol | 16.0 |
| Calcium gluconate | 33.0 |
| Low-substituted hydroxypropyl cellulose | 25.0 |
| Hydroxypropyl cellulose | 3.0 |
| Talcum powder | 3.0 |
| Total of | 100 |
Example 11
Mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A), microcrystalline cellulose, calcium hydrogen phosphate, anhydrous sodium carbonate, low-substituted hydroxypropyl cellulose and mannitol in a proportion shown in Table 7 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 7 example 11 table of the proportions of the components
Comparative example 1
Step 1: mixing mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound a), microcrystalline cellulose, calcium carbonate, low-substituted hydroxypropyl cellulose and mannitol in the proportion shown in table 8 by using a high-speed wet granulator to obtain a premix;
step 2: taking a water solution of hydroxypropyl cellulose as a binding agent, and granulating and drying the premix obtained in the step (1) and the binding agent to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles (with the moisture content less than 2%) obtained in the step (2), then adding the talcum powder with the prescription amount, and mixing by adopting a three-dimensional mixer to obtain the pharmaceutical composition of the Rankine. And (3) filling the obtained medical composition of the Rankine with capsules to obtain capsules.
Table 8 table of the proportions of each component in comparative example 1
| Composition (I) | Ratio (% by weight) |
| Compound A | 4.9 |
| Microcrystalline cellulose | 15.1 |
| Mannitol | 16.0 |
| Calcium carbonate | 33.0 |
| Low-substituted hydroxypropyl cellulose | 25.0 |
| Hydroxypropyl cellulose | 3.0 |
| Talcum powder | 3.0 |
| Total of | 100 |
Experimental example 1: dissolution test
The capsules of examples 1 to 11 and comparative example 1 were subjected to dissolution measurement according to the second method (paddle method) of dissolution measurement in the chinese pharmacopoeia 2020. A dissolution test was carried out using 900ml of a 0.1N (normality) hydrochloric acid solution as a dissolution medium at 37. + -. 0.5 ℃ and a rotation speed of 50 rpm. The dissolution data are shown in tables 9 and 10.
TABLE 9 dissolution data tables for examples 1-6
TABLE 10 dissolution data tables for examples 7-11 and comparative example 1
The dissolution rate results show that: the compound A in examples 1-5 (calcium bicarbonate), 6 (calcium hydrogen phosphate) and 9 (calcium citrate + calcium hydroxide) all dissolved out rapidly, wherein the dissolution rate of examples 1-5 in 15min can reach more than 90%. Compound a was not completely dissolved in example 7 (calcium phosphate), example 8 (calcium citrate), example 10 (calcium gluconate) and example 11 (calcium hydrogen phosphate + anhydrous sodium carbonate), and gelation occurred during dissolution. In comparative example 1, the compound A dissolved out in 15min only to 80% or more.
Experimental example 2: stability study
The capsules of examples 1 to 5, 6, 9 and 1 were placed in an atmosphere of 40 ℃/75% RH for six months, and the formation of degradation products was measured by HPLC. The stability data are shown in tables 11, 12 and 13.
The HPLC determination method comprises the following steps:
the specific process of the gradient method comprises the following steps:
table 11 degradation impurities (RRT 0.69) for examples 1-6, example 9 and comparative example 1 table
Table 12 table of degradation impurities (RRT 0.96) of examples 1 to 6, example 9 and comparative example 1
TABLE 13 general impurity table for examples 1-6, example 9 and comparative example 1
The stability results show that: in examples 1-5 (calcium bicarbonate), the degradation products (RRT ═ 0.69), the degradation products (RRT ═ 0.96) and the total impurities did not increase significantly, and in examples 6 (calcium hydrogen phosphate) and 9 (calcium citrate + calcium hydroxide), the degradation products increased significantly. Degradation products (RRT 0.69), degradation products (RRT 0.96) and total impurities were significantly increased in comparative example 1.
In conclusion, the quality of the pharmaceutical composition of the invention using calcium bicarbonate as the stabilizer is equivalent to that of comparative example 1 (i.e. the original preparation, calcium carbonate as the stabilizer), but the degradation impurities are significantly reduced.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition of Ranuncutinib, comprising the following components: an active drug and calcium bicarbonate, wherein the active drug comprises 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide represented by formula I or a pharmaceutically acceptable salt thereof;
preferably, the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide represented by formula I or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1, wherein the composition further comprises one, two or more of a diluent, a disintegrant, a binder, and a lubricant;
preferably, the composition comprises the following components: 1-30% of active medicine, 10-50% of calcium bicarbonate, 10-50% of diluent, 10-30% of disintegrating agent, 0-5% of adhesive and 0.5-5% of lubricant; the active medicine contains 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I or a pharmaceutically acceptable salt thereof, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the active drug is 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I or a pharmaceutically acceptable salt thereof;
preferably, the pharmaceutically acceptable salt of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide represented by formula I is the mesylate salt of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide.
Preferably, the diluent is selected from one or more of lactose, microcrystalline cellulose, starch (e.g. corn starch), mannitol, glucose, sucrose, modified starch (e.g. pregelatinized starch) and silicified microcrystalline cellulose;
and/or the presence of a gas in the gas,
the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrant, calcium carboxymethyl cellulose and carboxymethyl cellulose;
and/or the presence of a gas in the gas,
the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and copovidone;
and/or the presence of a gas in the gas,
the lubricant is selected from one or more of talcum powder, magnesium stearate, hydrogenated castor oil, glyceryl behenate and superfine silica gel powder.
Preferably, in the pharmaceutical composition of ranvatinib, the content of the active drug is 1.0% -10.0%;
and/or the presence of a gas in the gas,
in the pharmaceutical composition of Ranuncutinib, the content of calcium bicarbonate is 10.0-50.0%;
and/or the presence of a gas in the gas,
in the pharmaceutical composition of Ranuncutinib, the content of the diluent is 15.0-50.0%;
and/or the presence of a gas in the gas,
in the pharmaceutical composition of the Ranuncutinib, the content of the disintegrant is 20.0-30.0%;
and/or the presence of a gas in the gas,
in the pharmaceutical composition of Ranuncutinib, the content of the adhesive is 1.0-4.0%;
and/or the presence of a gas in the gas,
in the pharmaceutical composition of Ranuncutinib, the content of the lubricant is 1.0-4.0%.
3. The pharmaceutical composition of ranvatinib as claimed in claim 1 or 2, wherein: the pharmaceutical composition of Ranuncutinib comprises the following components: 1.0-10.0 percent of active medicine, 10.0-50.0 percent of calcium bicarbonate, 15.0-50.0 percent of diluent, 20.0-30.0 percent of disintegrant, 1.0-4.0 percent of adhesive and 1.0-4.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the pharmaceutical composition of ranvatinib comprises the following components: 4.9 percent of active medicine, 10.0 to 50.0 percent of calcium bicarbonate, 15.0 to 50.0 percent of diluent, 20.0 to 30.0 percent of disintegrant, 3.0 percent of adhesive and 3.0 percent of lubricant; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
preferably, the diluent is a mixture of microcrystalline cellulose and mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, and the lubricant is talc.
4. The pharmaceutical composition of ranvatinib as claimed in any one of claims 1-3, wherein: the pharmaceutical composition of Ranuncutinib is selected from any one of the following formulas:
the formula I is as follows: 4.9% of active drug, 33.0% of calcium bicarbonate, 15.1% of microcrystalline cellulose, 16.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and a second formula: 4.9% of active drug, 10.0% of calcium bicarbonate, 25.1% of microcrystalline cellulose, 24.0% of mannitol, 30.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and the formula III: 4.9% of active drug, 20.0% of calcium bicarbonate, 22.1% of microcrystalline cellulose, 22.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
the formula four: 4.9% of active drug, 40.0% of calcium bicarbonate, 12.1% of microcrystalline cellulose, 12.0% of mannitol, 25.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
and a fifth formula: 4.9% of active drug, 50.0% of calcium bicarbonate, 10.1% of microcrystalline cellulose, 9.0% of mannitol, 20.0% of low-substituted hydroxypropyl cellulose, 3.0% of hydroxypropyl cellulose and 3.0% of talcum powder; the active drug is a mesylate of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in formula I, wherein the percentage refers to weight percentage, and the weight percentage refers to the percentage of the weight of a single component in the total weight of the composition;
5. the pharmaceutical composition of ranvatinib as claimed in any one of claims 1-4, wherein: the pharmaceutical composition of the Ranuncutinib is a solid preparation.
Preferably, the solid preparation is a capsule, a tablet, a granule, powder, a sustained-release agent or a dropping pill.
6. The process for the preparation of the pharmaceutical composition of ranvatinib as claimed in any one of claims 1-4, comprising the steps of:
step 1: mixing an active drug, calcium bicarbonate, a diluent and a disintegrant to obtain a premix;
step 2: granulating and drying the premix obtained in the step 1 and an adhesive to obtain dry granules;
and step 3: and (3) carrying out dry granulation on the dry particles obtained in the step (2), and mixing with a lubricant to obtain the pharmaceutical composition.
7. A pharmaceutical formulation of Rankine comprising the pharmaceutical composition of any one of claims 1-4.
Preferably, the preparation is a solid preparation, such as a capsule, a tablet, a granule, a powder, a sustained-release agent or a dropping pill.
Preferably, the dissolution rate of the pharmaceutical formulation of Rankine at 15min is not less than 90%.
8. A process for the preparation of a pharmaceutical formulation of ranvatinib as claimed in claim 7, wherein said process comprises formulating said pharmaceutical composition.
Preferably, the process for the preparation of the pharmaceutical formulation of Rankine comprises the process for the preparation of the pharmaceutical composition of claim 6.
Preferably, the preparation method of the pharmaceutical preparation comprises: and (3) filling the pharmaceutical composition obtained in the step 3 in the preparation method of the pharmaceutical composition according to claim 6 into capsules to obtain capsules.
9. Use of the pharmaceutical composition of ranvatinib as claimed in any one of claims 1-4 or the formulation of claim 6 for the preparation of a medicament for the treatment and/or prevention of a tumor-related disease.
10. The use of claim 9, wherein: the tumor-related diseases are thyroid cancer, non-small cell lung cancer, melanoma, laryngopharynx cancer, esophageal cancer, gastric cancer, colorectal cancer, hepatocellular cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myelogenous leukemia, neuroma or glioma.
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